US3210386A - 3-aminoethers of 3beta-hydroxy androstanes - Google Patents

Description

United States Patent ()flice 3,210,386 S-AMINOETHERS F Sfl-HYDROXY ANDROSTANES Robert D. Birkenmeyer, Fred Kagan, Daniel Lednicer,

and Barney J. Magerlein, Kalamazoo, Mich., assignors to The Upjohn Company, Kalamazoo, Mich., a corporation of Delaware N0 Drawing. Filed Jan. 9, 1961, Ser. No. 81,270 7 Claims. (CL 260-397.3)

This invention relates to new steroid compounds and is particularly concerned With 3-aminoethers and 3- aminothioethers of 3fi-hydroxy steroids of the androstane series having the formulae:

3)u V- R and X i R N ''(CH2)D''V" R I wherein n has a value of 2 to 6, inclusive, wherein is selected from the group consisting of B CK and

011 -05, onvom wherein V is selected from the group consisting of the elements oxygen and sulfur; and wherein Y is selected from the group consisting of methyl and hydrogen.

Furthermore, in the above formulae when V is oxygen W is selected from the group consisting of O=CIJ l l and When V is, however, sulfur then W is selected from the group consisting of Patented Oct. 5, 1965 H I \C I and In the above formulae the parameter X is selected from the group consisting of HO AcO HO O=(|3; l 1 I and providing W is and V is oxygen.

Paramater X signifies also HO AcO HO O==(|1; l l l I and it HCEC/ when V is sulfur and W is When W is and V is oxygen, however, then X is selected from the group consisting of HO A00 no a p' a H, l H, l H8O and The term Ac in the above parameters refers to the acyl radical of a hydrocarbon carboxylic acid containing from one to eight carbon atoms, inclusive.

Furthermore; the invention relates to the N-oxides of the above defined products and the acid mineral salts of the above defined products, particularly the hydrochlorides and sulfates.

Additionally, the invention is concerned with the process of production for the above compounds.

The process of production of the compound of the structure shown above essentially comprises: conversion of a selected B-hydroxy-17-keto-andro-stane or 3-hydroxy- 17-keto-androstene to the 3-aminoether thereof with a selected amino-alkyl chloride by generally known procedures. Depending on the procedure chosen, it may be necessary to protect the 17-keto group of the starting compound of the androstane series, for example, by ketalization. In the event that it is desired to have a 11- keto steroid other as a final product, it will often be necessary to use a starting 3-hydroxy-17-keto steroid with an ll-oxy group and to oxidize this material to the corresponding ll-keto product after the ether linkage has been established.

To obtain 3-thioether, the same processes are carried out with a compound selected from the 3-meroaptoandrostane series.

The amino ether, obtained in the form of a salt, can be converted to the free basic amino ether by treatment with a base, and can be, if desired, converted to the salts of other acids by treating the free amino ether base with site? acids. Additional reactions after etherification inc u e:

( 1) Catalytic hydrogenation to convert A -androstene 3-ethers to the corresponding saturated androstane 3-ether.

(2) Conversion of 17 8-hydroxyl group to a 17fl-acy1oxy group by esterification.

(3) Conversion of the l7-keto group with a Grignard to the 17fi-hydroxy-17a-alkyl or ethynyl group.

(4) Conversion of the free tertiary amino steroid ether to its N-oxide.

The compounds produced by these reactions have hypocholesteremic activity. The compounds are thus useful in the treatment of atherosclerosis which is a form of arteriosclerosis which is characterized by the fatty degeneration occurring in the arterial walls, by mechanisms not yet definitely established. Hypercholesteremia refers essentially to an excess of cholesterol in the blood serum. While the causes of hypercholesteremia and the nature of its role in atherosclerosis and related conditions is not clearly understood, considerable effort has been directed toward reducing blood and tissue cholesterol levels as an attack upon the clinical conditions in which high levels are implicated. It has long been recognized that certain substances such as sitosterol, corn oil, and nicotinic acid are capable of reducing in small degree the blood and tissue cholesterol contents, either by interfering with the absorption of exogenous cholesterol introduced with food, or by facilitating the excretion of cholesterol from the body. Major emphasis, however, has been placed on the search for compounds which will interfere with the production of endogenous cholesterol by the liver and hence offer a more positive means of control of cholesterol levels.

The novel compounds of the present application significantly reduce the cholesterol content of both blood and tissue by partially arresting the biosynthesis of cholesterol in the body.

The new compounds, especially in their hydrochloric acid salt form, are also active against parasite-produced diseases in animals. They are particularly active against species of Trypanosoma, such as Trypanosama equiperdum and Trichomonas such as T richo mvnas vagirzalis, Entamoeba histo lytica, Entamoeba coli and against many of the eggs and larvae of common animal parasites. The novel materials, therefore, can be used against Trichomonas vaginalis, incorporated into suppositories or bougies or, can be used in sprays and as powders, in animal bedding, for cattle or poultry in order to prevent parasitic diseases.

Starting materials for this application, are materials such as dehydroepiandrosterone, dehydroepiandrosterone mercaptan [Bernstein, J. Org. Chem. 16, 679 (1951)], 3fi-hydroxy-6-methyl-17-keto-5-androstene [Greenville et al., J. Chem. Soc. (London), 4105 (1957)] and 11;?- hydroxy derivatives of the before-mentioned compounds prepared by methods shown in the preparations.

In carrying out the process of the present invention, the selected starting materials, 3-hydroxy-17-keto steroids, are dissolved in an organic solvent, and reacted with the selected di-N-substituted aminoalkyl chloride. The reaction is carried out in the presence of an alkali metal metathetically reactive reagent, such as triphenylmethyl sodium or triphenylmethyl potassium, metal hydrides such as sodium or potassium hydride or an alkyl alkali metal compound such as propyl or butyl lithium or propyl or butyl sodium, providing that in this event the 17-keto group must be protected by a keto-protecting group such as ketalor semic-arbazone formation.

The amount of the di-N-substituted amino alkyl chloride used in this reaction is preferably in excess of one mole (5-50%) per mole of steroid. The base alkali metal metathetically acting reagent is used in a ratio of 1.1 moles of base per mole of steroid. These quantities, however, are not critical and larger amounts can be used.

The ketal derivative which is used in the preferred embodiment of this reaction is usually produced by react ing the 17-keto steroid with glycols, wherein the total number of carbon atoms is up to 8, inclusive, and wherein the hydroxyl groups are on carbon atoms separated at the most by one methylene group.

The reaction mixture for the etherification is usually kept at reflux temperature, that is depending on the solvent between 60 and 120 C., and the period of reflux is usually about 2 to 24 hours. After the reaction is terminated, the product is recovered by conventional methods, that is by extraction, recrystallization or chromatography with organic solvents. Since the tertiary amino compound is easily converted to its hydrochloride, in which form it is water-soluble, it is usually extracted from the reaction mixture with aqueous hydrochloric acid. Ether can be added to the reaction mixture for better results in the extraction. Since the free amino base is found to be usually a viscous oil rather than crystalline material, the product is generally used in the form of its hydrochloric acid or sulfuric acid salts. Further chemical conversions of the thus-obtained amino-ethers are disclosed in the examples.

PREPARATION 1 3,6- (Zdiethylaminoethoxy -5-andr0sten-1 7 -one A 5 percent molar excess of sodium triphenylmethyl was added to a solution of 10 grams of dehydroepiandrosterone, dissolved in milliliters of benzene. A solution of 5.2 grams of diethylaminoethyl chloride, dissolved in 10.5 milliliters of toluene, was added to the reaction mixture which was then stirred at about 25 for one hour and heated at reflux temperature for two hours. The reaction mixture was filtered, the precipitate collected and suspended in about 200 milliliters of tetrahydrofuran. Five grams of diethylaminoethyl chloride, dissolved in 10 milliliters of toluene, was added and this mixture heated at reflux temperature for three hours. The reaction mixture was concentrated under vacuum and the residue dissolved in a mixture of benzene and water. The organic layer was washed three times with water, dried and concentrated under vacuum. The residue was dissolved in ether and gaseous hydrochloric acid bubbled into the solution. The precipitate which formed was collected, dried, dissolved in water, made alkaline and steam distilled. The residue was extracted with, ether,

dried and concentrated. The residual material was dissolved in ether and the ether solution extracted twice with dilute hydrochloric acid. The combined aqueous phases were neutralized with sodium hydroxide and extracted with methylene dichloride. The methylene dichloride extracts were concentrated under vacuum to yield 3.5 grams of a dark oil. One gram of this crude material was dissolved in methylene dichloride, placed on 100 grams of Florisil anhydrous magnesium silicate and eluted gradiently [Skellysolve B hexanes 100 percent to Skellysolve B hexanes 80 percent and 20 percent acetone at fraction 17, inclusive] collecting 200 milliliter fractions. Fractions 9 through 17, inclusive, were combined, dissolved in ether and ethereal hydrochloric acid added. The resulting precipitate was collected and recrystallized once from ethyl acetate and once from methanol-ether to a melting point of 194197 and a rotation of plus 17 in methanol.

Analysis-Calcd. for C H ClNO C, 70.80; H, 9.98; N, 3.30. Found: C, 70.63; H, 10.21; N, 3.49

PREPARATION 2 3 ,8- (Z-diethylaminoethoxy -5 -andrsten-1 7 one A mixture of 100 grams of dehydroepiandrosterone, 100 milliliters of ethylene glycol, 1500 milliliters of henzene and 2 grams of para-toluenesulfonic acid were heated under reflux for a period of five hours while removing water from the condensate with a trap. The reaction mixture was thereupon cooled to 30 degrees, washed with 200 milliliters of percent potassium bicarbonate solution, dried over sodium sulfate and finally 200 milliliters of benzene was distilled to complete the drying process. To the residue there was added 0.37 mole of butyl lithium, dissolved in hexane, followed by 0.38 mole of diethylaminoethyl chloride, dissolved in toluene. The reaction mixture was heated under reflux for 23 hours. The mixture was then cooled, diluted with 1 liter of ether and extracted with three successive 800 milliliter portions of dilute hydrochloric acid (80 milliliters of concentrated hydrochloric acid diluted with water to :800 milliliters). The aqueous extract was washed with 800 milliliters of ether. The combined organic extracts were dried and evaporated to yield 35 grams of recovered dehydroepiandrosterone.

The aqueous solution was extracted with 800 milliliter, 400 milliliter, and again 400 milliliter portions of methylene dichloride. These combined extracts were dried and concentrated. The residue was dissolved in a minimum of methylene dichloride and added to 2 liters of ether. The precipitate was collected by filtration, washed with ether and dried. 79 grams (53.8 percent yield) of 3,8(2-diethylaminoethoxy)-5-androsten-17-one was obtained.

PREPARATION 3 3B-hydr0xy-6 methyl-5 -andr0sten-1 7-0ne To a solution of 3.5 grams of 3B-hydroxy-6-methyl-5- androsten-17-one 3-acetate [J. Chem. Soc.(London) 4105 (1957)] in 30 milliliters of ethanol was added a solution of 80 milligrams of potassium hydroxide in two milliliters of water. The mixture was allowed to stand for a period of four hours under occasional shaking and was then poured into 150 milliliters of water. The solution was neutralized with dilute hydrochloric acid and the precipitate which was thus obtained was removed by filtration and washed with water. The material was twice recrystallized from methanol to get pure 3fi-hydroxy-6- methyl-S-androsten-17-one.

PREPARATION 4 313-mercapt0 6-methyZ-S-androsten-Z 7 -one A mixture of 2 grams of 3B-hydroxy-6-methyl-5- androsten-17-one, 5 milliliters of pyridine and 5 milliliters of paratoluenesulfonyl chloride was allowed to stand at room temperature for a period of four hours. Thereafter 6 the mixture was poured into 100 milliliters of water and this mixture was allowed to stand overnight in a refrigerator. The mixture was then filtered and the product recrystallized from methanol two times to give 318-ptoluenesulfonate of 3fi-hydroxy-6-methyl-S-androsten-17- one.

1.5 grams of 3fl-hydroxy-6-methyl-5-androsten-17-one 3-p-toluenesulfonate, 3 grams of thiourea, 1.8 milliliters of pyridine and 18 milliliters of ethanol were refluxed on a steam bath for four hours. The mixture was diluted with water and left in a refrigerator for 20 hours at a temperature of about 5 degrees centigrade. The thus precipitated crystals were collected, washed with 25 percent alcohol and percent water solution and thereupon recrystallized three times from methanol and acetone to give 3-isothiuronium p-toluenesulfonate of 35- hydroxy-6-methyl-5-androsten-17-one of formula:

CH3 a I NHg 314-- u 600 milligrams of the 3-(isothiuronium para-toluenesulfonate) of 3B-hydroxy-G-methyl-S-androsten 17 one was refluxed with a solution of 0.15 gram of sodium hydroxide in 15 milliliters of ethanol. To this mixture 1.2 milliliters of water were added and the mixture was refluxed for additionally 2 hours on a water-bath and thereafter poured into ice water. The mixture was acidified with glacial acetic acid whereupon a finally divided precipitate separated. The precipitate was collected, washed with water and recrystallized from benzene petroleum ether mixture to give pure 3fi-mercapto-6-methyl- 5-androsten-17-one.

PREPARATION 5 3,8,1 1 B-dihydroxy-S -androsten:-1 7 -one A medium was prepared containing per liter 20 grams of dextrose and 20 grams of corn steep liquor containing 12 grams of solid material. This medium was adjusted to a pH of 6.5 by the addition of sodium hydroxide and then sterilized. To 12 liters of such sterilized medium was added vegetative mycelium growth of Cunninghamella blakesleeana ATCC 9245, previously cultivated from spores. This medium was then incubated for 48 hours at 24 degrees centigrade. Thereupon was added 12 grams of 3fi-hydroxy-5-androsten-17-one and the incubation continued at 26 degrees Centigrade, under stirring and aeration for a period of 48 hours. Thereupon the fermentation mixture was filtered. The resulting cake was extracted with three four-liter portions of acetone which were added to the aqueous beer and the volume of the beer was reduced to one half, at 50 degrees centigrade under reduced pressure. To this mixture, approximately 12 liters, was now added 3 liters of acetone and this solution was filtered and then extracted five times with three liter portions of Skellysolve B hexanes to remove lipids resulting from the fermentation. The thus-obtained mixture was extracted four times with 5-liter volumes of ethylene dichloride. The ethylene dichloride extracts were combined, dried over anhydrous sodium sulfate and evaporated. The thus-produced residue was three times recrystallized from methanol and Skellysolve B hexane to give 35,11fl-dihydroxy-S-anclrosten-17-one.

7 PREPARATION 6 3,3,1 1 [3-dihydroxy-6-methyl-5 -andrsten-1 7-0ne In the same manner as shown in Preparation 5, 3(3- hydroxy-6-methyl-S-androsten-17-one is submitted to fermentation with Cunniltghamella blakesleeana and the fermentation mixture is extracted with water-immiscible organic solvents such as ethylene dichloride, methylene chloride, ether, benzene and the like to give 3,8,11,8-dihydroxy-6-methyl-5-androsten-17-one which is purified by either recrystallization from methanol, ethanol or mixtures of methanol and ethanol and hydrocarbons such as Skellysolve B hexanes, heptane, or the like.

7 PREPARATION 7 I 3B-mercapt0-11fl-hydroxy-6-methyl-S-aizdrosten-l 7-0110 In the same manner given in Preparation 4, 3,8,11fl-dihydroxy-6-methyl-S-androsten-17-one is converted to the 3fi-p-toluenesulfonate which by treatment with thiourea and pyridine produces the 3B-isothiuronium p-toluenesulfonate of 35,11,B-dihydroxy-6-methyl-5-androsten-17-one. Treatment of the isothiuronium toluenesulfonate with sodium hydroxide solution gave the 3Ii-mercapto-11flhydroxy-6-methyl-5-androsten-17-one.

In the same manner as shown in Preparation 7, the 3fi-mercapto-llfl-hydroxy-S-androsten-17-one was prepared.

EXAMPLE 1 3B- (Z-diethylaminoethoxy -5-andr0stcn-17,8-ol hydrochloride A solution of 6.0 grams of 35-(Z-diethylaminoethoxy)- 5-androsten-17-one hydrochloride in Water was made basic with solid sodium bicarbonate and the precipitate taken up in ether-benzene. The free base was obtained as an oily solid upon evaporation of the solvent in vacuo.

The thus-obtained free base, dissolved in 50 milliliters of tetrahydrofuran, was added to a well stirred suspension of 2.0 grams of lithium aluminum hydride in milliliters of tetrahydrofuran. The mixture was heated for 6 hours under reflux, then allowed to cool and the excess reagent destroyed with ethyl acetate. Water and ether were then added. The organic layer was separated, washed several times with water, dried over anhydrous sodium sulfate and evaporated to give a residue. This residue was taken up in ether and the ether solution was thereupon extracted with 0.5 normal aqueous hydrochloric acid. The solution of the aminoether hydrochloride in the aqueous acid was separated and washed with chloroform. The combined chloroform washings were evaporated to give 4.85 grams of crude product which was twice recrystallized from chloroform-ethyl acetate to give an analytical sample of 3,8-(2-diethylaminoethoxy)-5-androsten-17B-ol hydrochloride of melting point 258 to 261 degrees.

Analysis.Calcd. for C H ClNO C, 70.47; H, 10.41; N, 3.29. Found: C, 69.58; H, 10.39; N, 3.31.

EXAMPLE 2 3,a- (Z-diethylaminoeth oxy 7u-methyl-S-androsten- 17,8-01

A solution of 4.15 grams of 3,8-(2-diethylaminoethoxy)- 5-androsten-17-one in 100 milliliters of tetrahydrofuran was added to 40 milliliters of a 3 molar methylmagnesium bromide solution in ether. The resulting solution was heated under reflux for two hours and then allowed to stand at room temperature for 15 hours. The excess reagent was destroyed with water and ether was added. The organic layer was separated, washed well with water and dried with anhydrous magnesium sulfate. The solid which remained when the solvent was distilled was recrystallized twice from aqueous acetone to yield 2.30 grams of 3/3-(Z-diethylaminoethoxy)-l7amethyl-S-androsten-175-01 of melting point 118 to 120 C.

8 Analysis.-Calcd. for C H NO AH O: C, 76.51; H, 11.24; N, 3.43. Found: C, 76.37; H, 11.27; N, 3.58.

Further recrystallization from benzene and drying of the crystals in vacuo at C. gave water free material.

EXAMPLE 3 3 (3- (Z-di ethy laminoethoxy -1 7 a-ethyny l-5 -andr0sten- 1 -01 hydrochloride Acetylene was allowed to bubble through an ice-cold ether-free solution of methylmagnesium bromide in milliliters of tetrahydrofuran for a period of 45 minutes. To this solution there was added a solution of 3 8-(2- diethylaminoethoxy)-5-androsten-17-one in 100 milliliters of tetrahydrofuran. After 15 hours of heating under reflux, the mixture was allowed to cool and the excess reagent destroyed by adding water. Ether was thereupon added and the organic layer Washed well with water, followed by 0.5 N hydrochloric acid. The acid wash was then extracted with 600 milliliters of methylene chloride. The methylene chloride solution was evaporated and the resulting solids, 3.70 grams, was recrystallized twice from ethanol-ethyl acetate to yield 2.41 grams of 3B-(Z-diethylaminoethoxy)-17u ethynyl 5-androsten- -01 hydrochloride of melting point 251.5 to 253 de grees.

Some of this sample was recrystallized from ethanol to give a pure analytical sample of melting point 258- 260 C. However, the infrared spectrum of this sample showed it to be an ethanol solvate. Analysis for the ethanol solvate is as follows:

Analysis.-Calcd. for C27H44C1NO2.C2H5OHZ C, 70.21; H, 10.15; N, 2.82. Found: C, 70.26; H, 10.05; N, 3.47.

Treating 3/3-(2 diethylaminoethoxy)-17a-ethynyl-5- androsten-l7t3-ol hydrochloride in aqueous solution with potassium carbonate yields the free base, 3fi-(2-diethylaminoethoxy)-17a-ethynyl-5-androsten-176-01 which is recovered from the aqueous mixture by extraction with water-immiscible solvents and evaporation of the solvent.

EXAMPLE 4 36- (Z-diethy laminoethoxy) -5-andr0sten-1 7 -one N-oxide hydrochloride To a solution of 3B-(Z-diethylaminoethoxy)-5-androsten-l7-one hydrochloride (3.5 grams), dissolved in 20 milliliters of methanol, was added 10 milliliters of a 5 percent solution of sodium hydroxide in methanol. After swirling for 5 minutes the mixture was filtered and the filtrate evaporated to dryness under vacuum. The residue was dissolved in 100 milliliters of methylene dichloride which was then washed with three 25 milliliter portions of water. The methylene dichloride phase was filtered and then evaporated to dryness under vacuum, yielding 2.34 grams of the free base of the starting hydrochloride. This white solid material was dissolved in 10 milliliters of ethanol, cooled in an ice bath and 5 milliliters of 30 percent hydrogen peroxide solution added. After standing at about 25 degrees for 18 hours, the excess hydrogen peroxide was destroyed by portionwise addition of 500 milligrams of platinum oxide catalyst. Filtration and evaporation of the filtrate gave a white solid which was dissolved in ether. Hydrogen chloride gas was bubbled into this solution and the white solid which precipitated was collected, dried and recrystallized twice from acetone to give 3/3-(Z-diethylaminoethoxy)-5- androsten-17-one N-oxide hydrochloride of melting point 156 to 159.

Analysis-Called. for C H ClNO C, 68.23; H, 9.62; N, 3.18; Cl, 8.06. Found: C, 68.27; H, 9.78; N, 3.27; Cl, 8.16.

9 EXAMPLE 3,6- (Z-diethylamirzoethoxy -5a-andr0stan-1 7-one hydrochloride 318-(Z-diethylaminoethoxy)-5-androsten 17-one hydrochloride (1.1 grams) was dissolved in 200 milliliters of methanol and reduced in a Parr Hydrogenator at 30 to 50 psi. of hydrogen pressure using about 1 gram of 5 percent palladium on carbon as reduction catalyst. After one hour of the theoretical amount of hydrogen had been taken up, the reaction solution was filtered to remove the catalyst and the filtrate evaporated to dryness. The solid residue was recrystallized four times from a mixture of acetone-Skellysolve B hexanes to give 3,8-(2- diethylaminoethoxy)-5u-androstan-17-one hydrochloride monohydrate of melting point 164 to 165 degrees, with a yield of 500 milligrams.

Analysis.Calcd. for C H NO HCLH O: C, 67.76; H, 10.24; N, 3.16; CI, 8.00. Found: C, 67.81; H, 10.12; N, 3.29; Cl, 8.17.

Further heating to 60 C. in a vacuum desiccator resulted in the anhydrous material, Sfi-(Z-diethylaminoethoxy)-5ot-androstan-17-one hydrochloride.

EXAMPLE 6 3 ,8- (Z-diethy laminoethylth io -5 -androsten-1 7-0ne hydrochloride A mixture of 0.35 mole of 3/3-mercapto-5-androsten- 17-one, 100 milliliters of ethylene glycol, 1500 milliliters of benzene and 2 grams of p-toluenesulfonic acid were heated and refluxed for five hours. The water produced is removed from the reaction mixture by use of a water trap. The reaction mixture was then cooled to 30 degrees, washed with 200 milliliters of 5 percent potassium bicarbonate solution, dried over anhydrous sodium sulfate and finally 200 milliliters of benzene was distilled from this mixture to complete the drying process. To the dry benzene solution was added 0.37 mole of butyllithium, dissolved in hexane, followed after minutes by the addition of 0.38 mole of diethylaminoethyl chloride. The reaction mixture was heated at reflux temperature for 24 hours, cooled to 25 degrees, diluted with 1 liter of ether and extracted with three 800 milliliter portions of dilute hydrochloric acid (80 milliliters of 37 percent hydrochloric acid diluted to 800 milliliters). The aqueous extract was washed once with 800 milliliters of ether. The organic extracts were combined, dried over anhydrous sodium sulfate and evaporated to give the dry residue of the unreacted material.

The aqueous acidic phase was extracted with three 500- milliliter portions of methylene dichloride and these extracts were combined, dried and evaporated and the residue twice recrystallized from acetone to give, in 33 percent yield, 35-(Z-diethylaminoethylthio)-5-androsten-l7- one hydrochloride of melting point 186 to 189 degrees and rotation [11] plus 8 degrees.

Analysis.--Calcd. for C H ClNOS: C, 68.22; H, 9.62; N, 3.18; S, 7.29; CI, 8.06. Found: C, 67.78; H, 9.56; N, 3.23; S, 7.18; CI, 8.12.

EXAMPLE 7 3 5- (Z-diethylam inoethylthio -5 -androsten-l 7-one N -oxide hydrochloride To a mixture of 0.38 mole of diethylaminoethyl chloride, dissolved in 250 milliliters of ethanol and cooled in an ice-bath, was added 125 milliliters of 30 ercent hydro gen peroxide. After standing at about five degrees for 18 hours, the excess hydrogen peroxide was destroyed by the portion-wise addition of platinum oxide catalyst. After filtration, the solvent was evaporated in vacuo to yield crude diethylaminoethyl chloride N-oxide.

This crude diethylaminoethyl chloride N-oxide was added to a benzene solution of the lithium salt of 3,8- mercapto-S-androsten-l7-one 17-ethylene ketal, prepared as in Example 6. The reaction mixture was heated at reflux for 24 hours, cooled to room temperature, diluted with 1000 milliliters of ether and extracted with three portions of 750 milliliters of hydrochloride acid (one part 37 percent hydrochloric acid and nine parts water). The aqueous extract was washed once with 750 milliliters of ether. The aqueous acidic phase was extracted with three 500-milliliter portions of methylene dichloride, the extracts were combined, dried, evaporated and the thusobtained residue twice recrystallized from ethanol to give 3 8- Z-diethylaminoethylthio) -5-androsten-17-one N-oxide hydrochloride.

In the same manner given in Example 7, the N-oxides of dimethylaminoethyl chloride, diethylaminopropyl chloride, dimethylaminopropyl chloride, diethylaminobutyl chloride, dimethylaminobutyl chloride, diethylaminopentyl chloride, dimethylaminopentyl chloride, diethylaminohexyl chloride, dimethy-laminohexyl chloride can be made, which upon reaction with a selected lithium salt of 3,8- rnercapto-S-androsten-17-one 17-ketal, as shown in Example 7, result in the corresponding 3B-(2-dialkylaminoalkylthio)-5-androsten-17-one N-oxide hydrochloride.

Thus from:

(a) 3fl-mercapto-5-androsten-l7-one with diethylaminopropyl chloride N-oxide was obtained 3,8-(3-diethylaminopropylthio)-5-androsten-l7-one N-oxide hydrochloride.

(b) 3fl-mercapto-5-androsten-17-one with diethylaminobutyl chloride N-oxide was obtained 3/3(4-diet-hylaminobutylthio)-5-androsten 17 one N-oxide hydrochloride.

(c) 3 3-mercapto-5-androsten-17-one with diethylaminopentyl chloride N-oxide was obtained 35-(5-diethylaminopentylthio)-5-androsten-17-one N oxide hydrochloride.

(d) 3fi-mercapto-5-androsten-17-one with diethylaminohexyl chloride N-oxide was obtained 3,8-(6-diethyl- .aminohexylthio)-5-androsten l7 one N-oxide hydrochloride.

(e) 3B-mercapto-S-androsten-l7-one with dimethylaminobutyl chloride N-oxide was obtained 3B-(4-ditmethylaminobutylthio)-5-androsten l7 one N-oxide hydrochloride.

(f) 3,G-mercapto-S-androsten-l7-one with dimethylaminopentyl chloride N-oxide was obtained 3fi-(5-dimethylaminopentylthio)-5-androsten-l7-one N oxide hydrochloride.

(g) 3fl-mercapto-5-androsten-17-one with dimethylaminohexyl chloride N-oxide was obtained 3fl-(6-dimethylaminohexylthio)-5-androsten l7 one N-oxide hydrochloride.

(h) SB-mercapto-S-androsten-l7-one with morpholinylbutyl chloride N-oxide was obtained 3fi-(4-morpholinylbutylthio)-5-androsten-17-one N-oxide hydrochloride.

(1) SB-mercapto-l lfi-hydroxyl-S-androsten-l7-one with diethylaminoethyl chloride N-oxide was obtained 36-(2- diethylaminoethylthio) 11B hydroxyl-5-androsten-17- one N-oxide hydrochloride.

(j) 3fl-mercapto-l lB-hydroxyl-S-androsten-l7-one with diethylaminopropyl chloride N-oxide was obtained 3,8-(3- diethylaminopropylthio) 11,8 hydroxyl-S-androsten- 17-one N-oxide hydrochloride.

(k) Sfi-mercapto-llfl-hydroxyl-S androsten-17-one with diethylaminobutyl chloride N-oxide was obtained 318- (4-diethylaminobutylthio) 11B hydroxy-S-androstenl7-one N-oxide hydrochloride.

(1) 3,8-mercapto-11,8-hydroxyl-5 androsten-17-one with diethylaminopentyl chloride N-oxide was obtained 3,8- (S-diethylaminopentylthio) 1lfl-hydroxyl-S-androsten- 17-one N-oxide hydrochloride.

(in) BB-mercapto-llfi-hydroxyl-S androsten-l7-one with dimethylaminobutyl chloride N-oxide was obtained 3,8- 4-dirnethylarninobutylthio) -1 1 fi-hydroxyl-S-androstem 17-one N-oxide hydrochloride.

(n) 3fl-mercapto-l1;8-hydroxyl-5 androsten-17-one with dimethylaminohexyl chloride N-oxide was obtained 31i- (6-dirnethylaminohexylthio) -1 lfl-hydroxyl-S-androstenl7-0ne N-oxide hydrochloride.

() 3B-mercapto-1lfl-hydroxyl-S androsten-17-one with morpholinylhexyl chloride N-oxide was obtained 35-(6- morpholinylhexylthio)-1lfi-hydroxyl androsten-17- one N-oxide hydrochloride.

(p) 3 3-mercapto-6-methyl 5 androsten-17-one with diethylaminoethyl chloride N-oxide was obtained 3 8-(3- diethylaminoethylthio) -6-methyl-5audrosten-17-one N- oxide hydrochloride.

(q) 3fi-mercapto-6-methyl 5 androsten-17-one with diethylaminohexyl chloride N-oxide was obtained 3 8-(6- diethylaminohexylthio)-6-methy1 5 androsten-17-one N-oxide hydrochloride.

(r) 3B-mercapto-6-methyl-S-androsten-17-one with morpholinylhexyl chloride N-oxide was obtained 3,8-(6- morpholinylhexylthio)-6-methyl-5-androsten-17-0ne N- oxide hydrochloride.

(s) 3/3-n1ercapto-6-rnethyl-1lp hydroxy-5-androsten-17- one with diethylaminoethyl chloride N-oxide was obtained 35-(2 diethylaminoethylthio) 6 methyl-11,8- hydroxy-S-androsten-17-one N-oxide hydrochloride.

(t) 3/3-mercapto-6-rnethyl-11B hydroxy-5-androsten-17- one with diethylaminobutyl chloride N-oxide was obtained 35-(4 diethylaminobutylthio) 6 methyl-11,8- hydroxy-S-androsten-17-one N-oxide hydrochloride.

(u) 3,6-mercapto-6-rnethyl-1lfl-hydroxy-S-androsten 17- one with diethylaminohexyl chloride N-oxide was obtained 3B-( 6 diethylaminohexylthio) 6 methyl-11,8- hydroxy-S-androsten-17-one N-oxide hydrochloride.

(v) 3,8-mercapto-6-methyl-1lfi-hydroxy-S-androsten 17- one with dimethylaminohexyl chloride N-oxide was obtained 3 8 (6 dimethylaminohexylthio)-6-methyl-11flhydroxy-S-androsten-17-one N-oxide hydrochloride.

(w) 3fl-rnercapto-6-methyl-l1,8-hydroxy-5-androsten 17- one with morpholinylhexyl chloride N-oxide was obtained 3 6-(6-morpholinylhexylthio) 6-methyl-1lfi-hydroxy-5-androsten-17-one N-oxide hydrochloride.

EXAMPLE 8 3,8-(3-diethylaminoprop0xy) -5-andr0sten-17-one hydrochloride EXAMPLE 9 3 ,8- (2 -dimethylamin0ethoxy -5 -andr0sten-1 7 -one hydrochloride In the same manner given in Example 6, 3fi-hydroxy-S- andr0sten-17-one was converted with dirnethylaminoethyl chloride to 3B-(Z-dimethylaminoethoxy)-5-androsten-17- one of melting point 232 to 234 degrees.

Analysis.Calcd. for C23H33C1N02'H201 C, H, 10.22; N, 3.38; Cl, 8.57. Found: C, 69.47; H, 9.50; N, 3.56; Cl, 8.99.

EXAMPLE 10 3B- (Z-morpholinylethoxy -5-andr0sten-1 7-one hydrochloride In the same manner given in Example 6, 3fi-hydroxy-5- androsten-l7-one was converted with morpholinylethyl chloride to 3,8-(2-rnorpholinylethoxy) -5-androsten-17-one hydrochloride which when recrystallized from ethyl ace tate melted at 216 to 218 degrees centigrade with rotation [ab of plus 12 degrees in chloroform.

12 Analysis.-Calcd. for C H CINO C, 68.54; H, 9.20; N, 3.20; Cl, 8.10. Found: C, 67.91; H, 9.15; N, 3.35; CI, 8.15.

EXAMPLE 11 3 ,8- 2-diethylaminoethoxy -5 u-androstan-l 7 -one, N -0xidc, hydrochloride In the same manner as shown in Example 4, 3fi-(2-diethylaminoethoxy) -5a-androstan 17 one hydrochloride monohydrate was converted to 3B (2 diethylaminoethoxy)-5ot-androstan-17-one N-oxide, hydrochloride in 43 percent yield with a melting point of 151 to 153 degrees and rotation [ab of plus 47 degrees in chloroform.

Analysis.--Calcd. for C H CINO C, 67.92; H, 10.03; N, 3.17; Cl, 8.02. Found: C, 67.68; H, 10.16; N, 3.19; Cl, 8.09.

EXAMPLE 12 In the same manner given in Example 6, other 3-arninoethers and 3-thioarninoethers are obtained by converting a selected 3fi-hydroxy or 3B-mercapto-5-androsten-17-one to its respective l7-ketal, treating the ketal with an alkali metal metathetically active reagent, e.g., butyl lithium, sodium or potassium hydride, sodium trip'henylmethane and the like, and thereupon with a selected N-substituted amino-alkyl chloride. Thus from:

(a) 3/3-hydroxy-5-androsten-l7-one with diethylarninobutyl chloride was obtained 3,8-(4-diethylaminobutoxy)-5- androsten-17-one hydrochloride.

(b) 3,8-hydroxy-S-androsten-l7-one with diethylaminopentyl chloride was obtained 3B-'(S-diethylaminopentoxy)-5-androsten-l7-one hydrochloride.

(c) Elfl-hydroxy-S-androsten-l7-one with diethylaminohexyl chloride was obtained 3B-(6-diethylaminohexyloxy) -5-androsten-17-one hydrochloride.

((1) 3B-hydroxy-5-androsten-17-one with dimethylaminobutyl chloride was obtained 3B-(4-dimethylaminobutoxy)-5-androsten-17-one hydrochloride. hexyl chloride was obtained 3,8-(6-morpholinylhexyloxy)-5-androsten-17-one hydrochloride.

(e) 3 B hydroxy 5-androsten-l7-one with morpholinylbutyl chloride was obtained 3,8-(4-rnorpholinylbutoxy)- 5-androsten-17-one hydrochloride.

(f) 3,8-hydroxy-5-androsten-17-one with dimethylaminopentyl chloride was obtained 3fi-(5-dimethylaminopentoxy)-5-androsten-17-one hydrochloride.

(g) 3 3 hydroxy 5-androsten-17-one with morpholiny1- pentyl chloride was obtained 3,8-(5-morpholinylpentoxy)-5-androsten-17-one hydrochloride.

(h) 3B-hydroxy-5-androsten-17-one with dimethylaminohexyl chloride was obtained 3,8-(6-dimetl1ylaminohexyloxy)-5-androsten-17-one hydrochloride.

(i) 3 B hydroxy 5-androsten-17-one with morpholinyl- (j) 3 3-mercapto-S-androsten-l7-one with diethylaminopropyl chloride was obtained 3fi-(3-diethylaminopropylthio)-5-androsten-17-one hydrochloride.

(k) 3/3-rnercapto-5-androsten-17-one with diethylaminobutyl chloride was obtained 3/3-(4-diethylaminobutylthio -5-androsten-17-one hydrochloride.

(1') 3Bmercapto-S-androsten-l7-one with diethylaminopentyl chloride was obtained 3,8-(S-diethylarninopentylthio)-5-androsten-17-one hydrochloride.

(in) 3B-mercapto-5-androsten-17-one with diethylaminohexyl chloride was obtained 3 8-(6-diethylarninohexylthio)-5-androsten-17-one hydrochloride.

(11) 3B mercapto-S-androsten-17-one with dimethylaminobutyl chloride was obtained 3,8-(4-dimethylaminobutylthio)-5-androsten-17-one hydrochloride.

(0) 3/3 -mercapto-S-androsten-17-one with dimethylaminopentyl chloride was obtained 3 8-(5-dimethylaminopentylthio)-5-androsten-l7-one hydrochloride.

(p) 3B-mercapto-S-androsten-17-one with dimethylaminohexyl chloride was obtained 3fl-(6-dimethylaminov hexylthio)-5-androsten-l7one hydrochloride.

(q) 3,8-mercapto-S-androsten-17-one with morpholinyl- 13 butyl chloride was obtained 35-(4-morpholinylbutylthio)-5-androsten-17-one hydrochloride.

(r) 35-mercapto-S-androsten-l7-one with morpholinylpentyl chloride was obtained 35-(5-morpholinylpentylthio)-5-androsten-l7-one hydrochloride.

(s) 35-mercapto-S-androsten-17-one with morpholinylhexyl chloride was obtained 35(6-morpholinylhexylthio)-5-androsten-l7-one hydrochloride.

Example 13 In the same manner given in Examples 6 and 7, 11-oxygenated 3-arnino ethers and ll-oxygenated 3-aminothioethers are obtained by converting a selected 35,115-dihydroxy or 35-rnercapto-l15-hydroXy-5-androsten-17-one to its respective ketal, treating the ketal with butyl lithium and thereupon with a selected N-substituted amino alkyl chloride. Thus from:

(a) 35,115 dihydroxy-S-androstem17-one with diethylaminoethyl chloride was obtained 35-(2-diethylaminoethoxy) 115 hydroxy-S-androsten17-one hydrochloride.

(b) 35,115 dihydroxy-S-androsten-l7-one with diethylaminopropyl chloride was obtained 35-(3-diethy1aminopropoxy) 115-hydr0xy-5-androsten-17-one hydrochloride.

(c) 35,115 dihydroxy-S-androsten-17-one with diethylaminobutyl chloride was obtained 35-(4-diethylaminobutoxy) 1=15 hydroxy-S-androstend7-one hydrochloride.

(d) 35,115 dihydroxy-S-androsten-17-one with diethylaminopentyl chloride was obtained 35-(5-diethylaminopentoxy) 115-hydroXy-5-androsten-17-one hydrochloride.

(e) 35,115-dihydroxy-S-androsteml7-one with diethylaminohexyl chloride was obtained 35-(6-diethylaminohexyloxy)-115-hydroxy-5-androsten-17-one hydrochloride.

(f) 35,115-dihydroXy-5-androsten-17-0ne with dirnethylaminobutyl chloride was obtained 35-(4-dimethylaminobutoxy)-115-hydroxy-5-androsten-17-one hydrochloride.

(g) 35,115 dihydroxy-S-androsten-17-one with morpholinylbutyl chloride was obtained 35-(4-morpholinylbutoxy) 115 hydroxy-S-androsten-17-one hydrochloride.

(h) 35,115-dihydroXy-5-androsten-17-one with dirnethylaminopentyl chloride was obtained 35-(5-dirnethylaminopentoxy) 115 hydroxy-S-androsten-17-one hydrochloride.

(i) 35,115- dihydroXy5-androsten-17-one with morpholinylpentyl chloride was obtained 35-(5-morpholinylpentoxy) 115-hydroXy-5-androsten-17-one hydrochloride.

(j) 35,115-dihydroXy-5-androsten17-one with dirnethylaminohexyl chloride was obtained 35-(6-dimethylaminohexyloxy) 115 hydroxy-S-androsten-17-one hydrochloride.

(k) 35,115-dihydroXy-5-androsten-l7-one with morpholinylhexylchloride was obtained 35-(6-morphovlinylhexy1oXy)-1 15-hydroxy-5-androsten-17-one hydrochloride.

(1) 35-rnercap'to-115-hydroXy-5-androsten-17-one with diethylaminoethyl chloride was obtained 35-(2-diethylaminoethylthio -1 15-hydroxy-5-androsten-17-one hydrochloride.

(in) 35-mercapto-115-hydroxy-5-androsten-17-one with diethylaminopropyl chloride was obtained 35-(3- diethylaminopropylthio)-115-hydroxy-5-androsten- 17-one hydrochloride.

(n) 35-mercapto-115-hydroxy-5-androsten-17-one with diethylaminobutyl chloride was obtained 35- (4- diethylaminobutylthio -1 15-hydroXy-5-androsten- 17-one hydrochloride.

() 35-rnercapto-115-hydroXy-S-androsten-17-0ne with diethylaminopentyl chloride was obtained 35-(5- 14 diethylaminopentylthio -1 1 5-hydroxy-5-androstenl7-one hydrochloride.

(p) 3 5-mercapto-1 15-hydroXy-5-androsten-17-one with diethylaminohexyl chloride was obtained 35- 6-diethylarninohexylthio -1 15-hydroxy-5- androsten-l7-one hydrochloride.

(q) 35-mercapto-1 15-hydroXy-5-androsten-17-one with dimethylaminobutyl chloride was obtained 3 5- (4-dimethylaminobutylthio -1 15-hydroxy- 5-androsten-17-one hydrochloride.

(r) 35-mercapto-115-hydroxy-5-androsten-17-one with dimethylaminopentyl chloride was obtained 35-(5-dimethylaminopentylthio)-115-hydroxy 5-androsten-l7-one hydrochloride.

(s) 35-mercapto-ll5-hydroxy-5-androsten-l7-one with dimethylaminohexyl chloride was obtained 35-(6-dimethylaminohexylthio -l 15-hydroxy-S-androsten- 17-one hydrochloride.

(t) 35-rnercapto-115-hydroxy-5-androsten-17-one with morpholinylbutyl chloride was obtained 35-(4-morpholinylbutylthio -1 15-hydroxy-5-androster1- l7-one hydrochloride.

(u) 35-rnercapto-1l5-hydroxy-5-androsten-17-one with morpholinylpentyl chloride was obtained 35-(5- n1 orpholinylpentylthio -1 15-hydroXy-5-androste11- 17-0ne hydrochloride.

(v) 35-rnercapto-115-hydroxy-5-androsten-17-one with morpholinylhexyl chloride was obtained 35-(6- morpholinylheXylthio)-l15-hydroXy-5-androsten- 17-one hydrochloride.

EXAMPLE 14 In the same manner given in Examples 6 and 7, 3- arnino-6-methyl ethers and thioethers are obtained by converting selected 3 5-hydroxy-6-methylor 35-rnercapto- 6-methyl 5 androsten-17-ones, 35,115-dihydroxy-6- methylor 35-rnercapto- 6-rnethyl-l15-hydroXy-5-androsten-17-ones to its respective ketals, treating the kctals with butyl lithium and thereupon with a selected N-substituted amino alkyl chloride. Thus from:

(a) 35-hydroXy-6-rnethyl-S-androsten-17-one with diethylaminoethyl chloride was obtained 35-(2-diethylaminoethoxy) -6-methyl-5-androsten-l7-one hydrochloride.

(b) 35-hydroxy-6-methyl-5-androsten-17-one with diethylaminobutyl chloride was obtained 35-(4- diethylaminobutoxy) -6-methyl-5-androsten-17- one hydrochloride.

(c) 35hy droxy-6-methyl-5-androsten-l7-one with diethylaminohexyl chloride was obtained 35-(6- diethylaminohexylo-Xy 6-methyl-5-androsten 17-one hydrochloride.

((1) 35-hydroxy-6-methyl-5-androsten-17-one with dirnethylaminobutyl chloride was obtained 35-(4- dimethylarninobutoxy 6-rnethyl-5-androstenl7-one hydrochloride.

(e) 35-hydroxy-G-methyl-S-androsten-17-one with morpholinylethyl chloride was obtained 35-(4- morpholinylethoxy) -6-methyl-5-andr0sten- 17-one hydrochloride.

(f) 35-hydroxy-6-rnethyl-5-androsten-17-one with dimethylaminohexyl chloride was obtained 35-(6- dimethylaminohexyloxy) -6-methyl-5-androsten- 17-one hydrochloride.

(g) 35-rnercapto-6-methy1-5-androsten17-one with diethylaminoethyl chloride was obtained 35-(3- diethylaminoethylthio) -6-methyl-5-androstenl7-one hydrochloride.

(h) 35-n1ercapto-6-methyl-5-androsten-17-0ne with diethylaminobutyl chloride was obtained 35-(4- diethylaminobutylthio 6-methyl-5-androsten- 17-one hydrochloride.

(i) 35-mercapt0-6-methyl-5-androsten-17-one with diethylaminohexyl chloride was obtained 35-(6- diethylaminohexylthio -6-methyl-5-androsten- 17-hydrochloride.

(j) 36-mercapto-G-methyl-S-androsten-17-one with dimethylaminohexyl chloride was obtained 36- (6-dimethylaminohexylthio -6-methy15 -androsten- 17-one hydrochloride.

(k) 36-mercapto-6-methyl-5-androsten-17-one with morpholinylhexyl chloride was obtained 36-(6- morpholinylhexylthio) -6-methyl-5-androsten- 17-one hydrochloride.

(1) 36,116-dihydroxy-6-methyl-5-androsten-17-one with diethylaminoethyl chloride was obtained 36-(4- diethylaminoethyl) -6-methyl-1 16-hydroxy-5- androsten-17-one hydrochloride.

(m) 36,116-dihydroxy-6-methyl-S-androsten-17-one with diethylaminohexyl chloride was obtained 36- (6-diethylaminohexyloxy) -6-methyl- 1 16-hydroxyandrosten-17-one hydrochloride.

(11) 36,1 1,B-dihydroxy-6-methyl-5-androsten-17-one with dimethylaminobutyl chloride was obtained 36- 4-dimethylaminobutoxy -6-methyl-1 16-hydroxy- 5-androsten-17-one hydrochloride.

( o) 36,116-dihydroxy-6-methyl-5-androsten-17-one with dimethylaminohexyl chloride was obtained 3 6- (6-dimethylaminohexyloxy -6-methyl-1 16- hydroxy-S-androsten-17-one hydrochloride.

(p) 36,116-dihydroxy-G-methyI-S-androsten-17-one with morpholinylhexyl chloride was obtained 3 6- 6-morpholinylhexyloxy -6-methyl-1 16-hydroxy- 5-androsten-17-one hydrochloride.

(q) 3 6-mercapto-6-methyl-1 16-hydroXy-5-androsten- 17-one with diethylaminoethyl chl-oride was obtained 3 6- Z-diethylaminoethylthio 6-methyl-1 16- hydroxy-S-androsten-l7-one hydrochloride.

(r) 3 6-mercapto-6-methyl-1 16-hydroXy-5-androsten 17-one with diethylaminobutyl chloride was obtained 36-(4-diethylaminobutylthio)-6-methyl- 116-hydroxy-5-androsten-17-one hydrochloride.

(s) 36 mercapto-6-methyl-116-hydroXy-5-androsten-17- one with diethylaminohexyl chloride was obtained 36- (6 diethylaminohexylthio) 6 methyl-116-hydroxy-5- androsten-17-one hydrochloride.

(t) 36 mercapto-6-methyl-116-hydroxy-5-androsten-l7- one with dimethylaminohexyl chloride was obtained 36 (6 dimethylaminohexylthio) 6 methyl-116-hydroxy-5-androsten-17-one hydrochloride.

(u) 36 mercapto-6-methyl-116 hydroxy-5-androsten-17- one with morpholinylhexyl chloride was obtained 36- (6 morpholinylhexylthio) 6 methyl-116-hydroxy-5- androsten-17-one hydrchloride.

The amino ethers and the amino thioethers of EX- amples 12, 13 and 14 obtained as hydrochlorides can be obtained as free bases by adding to the aqueous solution of the amino ether hydrochloride or the amino thioether hydrochloride a base such as sodium hydroxide, sodium bicarbonate, potassium hydroxide, potassium carbonate and bicarbonate and the like and extracting the aqueous mixture with water-immiscible solvent such as ether, benzene, methylene chloride, hexanes and the like. The thus-obtained solution is further washed with water, then dried and evaporated, giving the amino ether as free base.

EXAMPLE 15 36- (Z-diethylaminoethylthio) 7ot-methyl-5- androsten-J 7 6-01 In the same manner given in Example 2, two grams of 36-(Z-diethylaminoethylthio)-5-androsten-17-one in tetrahydrofuran was added to 40 milliliters of a 3 molar methyl magnesium bromide solution in ether. The resulting solution was heated under reflux for two hours and allowed to stand over night for a period of about hours. Thereupon the excess reagent was destroyed with water and the aqueous reaction mixture extracted with ether. The ether solution was washed several times with water, then evaporated and the solids obtained recrystallized from aqueous acetone to yield 36-(2-diethylaminoethylthio)-17a-methyl-5-androsten-176-01.

1 e EXAMPLE 16 3 6- Z-d z'ethylaminoethyl t/z i0) -1 7 a-ethynyl-5 -andr0sten- 176-0l hydrochloride In the same manner given in Example 3, acetylene was allowed to bubble through an ice-cold ether-free solution of methyl magnesium bromide in tetrahydrofuran. To this solution was then added 36-(2-diethylaminoethylthio)-5-androsten-17-one in tetrahydrofuran. After heating for 15 hours, the excess reagent was destroyed by the addition of water and the reaction mixture extracted with ether. The ether solutions were washed with water, then with hydrochloric acid and the aqueous acid wash was then extracted with 600 milliliters of methylene chloride. The methylene chloride solution was evaporated and the resulting solids recrystallized from ethanol and ethyl, acetate to yield 36-(Z-diethylaminoethylthio)-17a-ethynyl-5- androstcn-l76-0l hydrochloride.

EXAMPLE 17 36- (Z-diethylaminethoxy -6,1 t-diI716fllyl-5 andr0sten-176-0l In the same manner given as in Example 15, from 36- (2-diethylaminoethoxy)-6-methyl-5-androsten-l7-one with methyl magnesium bromide was obtained 36-(2-diethylaminoethoxy)-6,l7ot-dimethyl-S-androsten-176-01.

EXAMPLE 18 36-(2-diethylamin0eth0xy -6,1 7a-dimethyl-1]6,1 76- dillydroxy-S-androsten In the same manner given in Example 15, 36-(2-diethylaminoethoxy)-6-methyl-5-androsten-17-one is treated with methyl magnesium iodide to give 36-(2-diethylaminoethoxy)-6,17a-dimethyl-116,176-dihydroxy-S-androsten.

EXAMPLE 19 36- (Z-diethylaminoerhylthio 6,] 7a-dimethyl-116J 76- dihydroxy-S-androsten In the same manner given in Example 15, 36-(2-diethylaminoethylthio)-6-methyl-116-hydroXy-5-androsten 17- one gave with methyl magnesium iodide 36-(2-diethylaminoethylthio) 6 17a-din1ethyl-116,176-dihydroXy-5- androsten.

EXAMPLE 20 Substituting in Example 15, the starting steroid with 36- (2 diethylaminoethylthio) 6 methyl-l16-hydroxy 5- androsten-17-one results in the production of 36-(2-diethylaminoethylthio)-6-methyl 17ot-ethynyl-116,176 dihydroxy-S-androsten.

In the same manner as shown in Example 15, other l7ot-methyl steroids can be prepared from the 3-amino and 3-thio amino 17-ketal ethers such as, for example: 36- (3-diethylaminopropoxy )-17a-methyl-5-androsten- 3 6- 4-diethylaminobutyloxy 17ot-methyl-5 -androsten- 36- 6-diethylaminohexyloxy 17a-methyl-5-androsten- 36- (Z-dimethylaminoethoxy 17u-methyl-5-androsten- 3 6- 4-dimethylaminobutyloxy 1 7ot-methyl-5-androsten- 176-01- 36-(5-dimethylaminopentyloxy)-17a-methyl-5-androsten- 36- Z-dimethylaminoethoxy -1 16,176-dihydroxy-17otmethyl-S-androstene; 36-(3-diethylaminopropoxy)-6,17ot-dimethyl-5-androsten- 3 6- (4-diethylaminobutyloxy -6- 17ot-dimethyl-5-androsten- 36- 6- diethylaminohcxyloxy) -6, l7oz-dimethyl-5-androsten-l76-ol; 36-(3-diethy1amin0propylthio)-17a-methyl-5-androstenl 7 3 ti- (4-diethylaminobutylthio 17a-methy1-5androsten- 17fi-ol; 3[5-(6-dimethylaminohexylthio )-6,17a-dimethyl-1 113,175-

dihydroxy-S-androstene; 313- 4-dimethylaminobutylthio -6, 17a-dimethyl1 1,8,17,8-

dihydroxy-S-androstene; and the like.

EXAMPLE 21 A mixture is prepared consisting of milliliters of pyridine, 5 milliliters of acetic anhydride and 1' gram of 3,8-(2- diethylaminoethoxy)17u-methyl 5 androsten 17B 01. This mixture was allowed to stand at room temperature with occasional shaking for a period of 4 hours. The mixture was thereupon poured into ice-Water and allowed to stand over night. The material which had separated from it was collected on filter paper, washed repeatedly with water and then recrystallized from methanol to give 3fl-(2-diethylaminoethoxy)-17a-methyl-5-androsten 17/3- 01 17-acetate.

Replacing in Example 21, the acetic anhydride by propionic butyric valeric, hexanoic, heptanoic, benzoic, phenylacetic or phenylpropionic anhydride or by an acid chloride such as ,B-cyclopentylpropionic, benzyl chloride, lauroyl chloride, results in the production of the corresponding l7-propioninate, butyrate, valerate, exanerate, octynrate, benzorate, phenyl-acetate, phenyl-propionate, B-cyclopendylpropionate, laurate and the like esters of the corresponding 3B-(2-diethylaminoethoxy)- 17a-methyl-5-androsten-173-01.

In the same manner the acetate, propionates, butyrates, hexanoates, benzoates and other hydrocarbon carboxylic acid esters may be prepared of other Not-methyl and 17u-ethynyl, 17fi-hydroXy-5-androstenes having an ether group such as Z-diethylaminopropoxy, Z-diethylaminobutyloxy, Z-diethylaminoethylthio, Z-diethylaminopropylthio, 2 diethylaminohexylthio and the like.

EXAMPLE 22 3 ,9- (Z-diethylaminopro poxy -5 a-androstan-l 7-0ne hydrochloride monohydrate In the same manner given in Example 5, hydrogenating 3,8-(Z-diethylaminopropoxy) -5-androsten-17 one hydrochloride in methanol with hydrogen in the presence of a palladium catalyst on a carbon carrier produces the 3B-(2-diethylaminopropoxy)-5a-androstan-17-one hydrochloride.

In the same manner as shown in Example 5, other 3- amino and 3-aminothio ethers of unsaturated steroid, as prepared in the foregoing examples, can be reduced to give the corresponding saturated 3-aminoand 3-thioamino steroid ethers. Representative products such produced include:

3 ,9-(2-diethylaminoethoxy)-1 1 B-hydroxyandrostan- 17-one hydrochloride;

3/3-(Z-diethylaminoethoxy)-6-methyl-11B- hydroxyandrostan-17-one hydrochloride;

3/3-(3-diethylaminopropoxy)-1lfi-hydroxyandrostan- 17-one hydrochloride;

3 ,8- 3-diethylaminoprop oxy) -6ot-rnethyl-1 1 ,B-hydroxyandrostan-17-one hydrochloride;

3 B- (4-diethylaminobutyloxy -1 l B-hydroxyandrostan- 17-one hydrochloride;

35-(4-diethylaminobutyloxy)-6ot-methyl11,8-hydroxyandrostan-l7-one hydrochloride;

315'-(S-diethylaminopentyloxy)-1 lfl-hydroxyandrostan- 17-one hydrochloride;

3(3- (S-diethylaminopentyloxy) -6a-methyl-1 1 B-hydroxyandrostan-l7-one hydrochloride;

3 B-(6-diethylaminohexyloxy)-1 IB-hydroxyandrostan- 17-one hydrochloride; 7

3 5- fi-diethylaminohexyloxy) -6 a-methyl-l 1 fi-hydroxy androstan-17-one hydrochloride;

3 ,6- 2-dimethylaminoethylthio -1 1 8-hydroxyandrostan- 17-one hydrochloride;

3,8-(Z-diethylaminoethylthio)-1lfi-hydroxyandrostan- 17-one hydrochloride;

3 5- 3-d-iethylaminopropylthio)-1 1 B-hydroxyandrostan- 17-one hydrochloride;

3 ,8- 6-diethylaminohexylthio -1 1 ,B-hydroxyandrostan- 17 -one hydrochloride;

3 8- 2-morpholinylethylthio -6u-methyl- 1 1,8-hydroxyandrostan-17-one hydrochloride;

3 ti- 5-morpholinylpentylthio -6u-methyl-1 I/S-hydroxyandrostan-17-one hydrochloride;

3,8- B-dimethylaminopropylthio)-6u-methyl-1 1 3,175-

dihydroxyandrostane hydrochloride;

3,6-(3-dimethylaminopropylthio)-6u,17ot-d]imethyl-11 8,

17B-dihydroxyandrostane hydrochloride;

3 ,8- 3-dimethylaminopropylthio) -6a-methyl-17u-ethynyl- 1 1 6,17,8-dihydroxyandrostane hydrochloride;

3B-(4-dimethylaminobutyloxy)-6a-rnethyl-11B,17B-dihydroxyandrostane hydrochloride, 17a-acetate;

3,8- (4-dimethylaminobutyloxy)-6a-methyl-l 1B, 17B-di hydroxyandrostane hydrochloride, 17a-phenylacetate;

3,8-(4-dimethylaminobutyloxy)-6a-methyl-11fi3,17fidihydroxyandrostane hydrochloride, 17a-(3-cyclopentylpropionate) and the like.

EXAMPLE 23 3,8-diethylaminoeth0xy-5-andr0sten-l1,17-di0ne A solution was prepared containing 5 milliliters of glacial acetic acid, 200 milligrams of chromic anhydride and /2 milliliter of water. Into this solution at room temperature (22 to 24 degrees Centigrade) was introduced 300 milligrams of 3B-(2-diethylaminoethoxy)-11,8,17B- dihydroxy-S-androstene. The mixture was allowed to stand at room tempearture for a period of four hours and was thereupon poured into 50 milliliters of ice-water. The ice-water solution was neutralized by the addition of 10 percent sodium bicarbonate solution. The mixture was thereupon extracted with three 25-milliliter portions of chloroform, the chloroform extracts were combined, repeatedly washed with water until neutral, dried over anhydrous sodium sulfate and evaporated. The thus-obtained residue was recrystallized three times from methanol to give 35-(Z-diethylaminoethoxy)-5-androsten 11,17-dione.

EXAMPLE 24 3 B- (2-diethylaminoethovcy 7ot-methyl-5-androstena 11 -one In the same manner given in Example 23, Sfi-(Z-diethylaminoethoxy) 17a-methy1-11/3,17,8-dihydroxy-5-androsten was oxidized with chromic anhydride in acetic acid to give 35-(Z-diethylaminoethoxy)-17u-methyl-17,8-hy droxy-S-androsten-l l-one.

EXAMPLE 25 3B- (Z-dimethyIaminoethoxy 7B-hydr0xy-5-androsten- J 1 -0m2 17-acetate In the same manner given in Example 23, 3fi-(2-dimethylaminoethoxy)-l1[3,17B dihydroxy 5 androsten 17-acetate was oxidized with chromic acid to give 35- (Z-dimethylaminoethoxy) 17B hydroxy-5-androsten-1l one 17-acetate.

In the same manner given in Example 23, other 3- amino-llB-hydroxy steroid ethers can be oxidized to give the corresponding ll-keto ethers of the 3-amino steroids. Representative compounds such produced include:

3 ,8- 4-diethylaminobutyloxy) -5-androsten-1 1,17-dione;

3 B-(6-diethylaminohexyloxy)-5-androsten-11,17-dione;

3 5-( 2-diethylaminoethoxy) -6-methyl-5-androsten-1 1,17-

dione;

3 fi- 3-diethylarninopropoxy -6-methyl-5-androsten- 11,17-dione;

EXAMPLE 27 3,8- (Z-diethylaminoethoxy 7a-methyl-5-andr0sten 1 7 fl-ol sulfate A solution of 0.5 gram of 3/3-(Z-diethylaminoethoxy)- 17a-methy1-S-androsten-175-01 (Example 2) in 10 milliliters of acetone was titrated with a 10 percent sulfuric acid solution in water. Titration was stopped at a pH of about 6.5 and the solution was evaporated. The product was washed with ether and Skellysolve B hexane, the washing discarded and the material twice recrystallized from alcohol to give SB-(Z-diethylaminoethoxy)-17ormethyl-S-androsten-1718-01 sulfate.

In the same manner, other mineral acid salts can be prepared from the 3-arnino ethers and 3-aminothio ethers in the free-base state by reacting the selected amino steroid with the stoichiometric quantity of a mineral acid, e.g., hydrobromic, nitric, phosphoric or the like.

We claim:

1. A compound selected from the group consisting of (1) those having the formulae is selected from the group consisting of W is selected from the group consisting of and 0:3)

X is selected from the group consisting of fit 01-: uzon wherein n has a value of 2 to 6, inclusive;

is selected from the group consisting of H30 H C2 OI-I CH N, N and O 1-1 0 CHgp-Cfig W is selected from the group consisting of t, and O=C|1 l I Y is selected from the group consisting of hydrogen and methyl, and (2) a mineral acid salt thereof.

3. 35 (Z-diethylamindethoxy)-17a-ethyl-5-androstenl7B-ol-hydrochloride.

4. 3B (Z-diethylarninoethylthio)-5-androsten-l7-one hydrochloride.

5. 3e (Z-diethylarninoethoxy)-6-methyl-l7a-ethynyl- 5 -androsten-l7 [3-01 hydrochloride.

6. 35 (4 diethylaminobutoxy)-l7x-ethyl-5-andro sten-l7 8-ol hydrochloride.

7. In a process for the production of steroid compounds selected from the group consisting of compounds of Formula I:

wherein V is selected from the group consisting of the elements oxygen and sulfur; wherein W is selected from the group consisting of when V is oxygen; and wherein W is selected from I0 and when V is sulfur; wherein X is selected from the group consisting of HO AcO\ HO O\ CH; 1 \JJ: (E; (J and A: i I l O O H H H30 HG C 5 when W is 1 CH3 110 o=r|3 and 0 and when V is oxygen; and when W is a Y (II) wherein R is an alkylene group with up to eight carbon atoms and wherein the carbon atoms attached to the oxy- C and 0 gen bonds are separated by not more than one methylene group and V and Y have the same significance as in the Formula I, consecutively (1) with an alkali metal metathetically acting agent and (2) with an alkyl chloride and when Vls Sulfur; and selected from the group consisting of compounds of the wherein X is selected from the groups consisting of formula:

HO AcO HO HO J \& I and t N- o1'12 no1 H" i H" I H 0" I H050" I R nd when W is a R o III(OH2),.C1

wherem the parameters and when V is oxygen; wherein Y is selected from the group consisting of methyl and hydrogen; and R wherein Ac is the acyl radical of a hydrocarbon carboxylic acid containing from one to eight carbon and n are defined as above. atoms, inclusive;

and, the N-oXides and the mineral acid salts thereof selected from the group of mineral acids consiting of LEWIS GO'ITS, Primary Examiner h drochloric, h drobromic, sulfuric, nitric and phosphoric acid, the steps which comprise: treating a compound of LESLIE GASTON MORRIS LIEBMAN the structure II No references cited.

Claims (1)

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF (1) THOSE HAVING THE FORMULAE